Method of producing aralkyl cyanides



IVIETHOD F PRODUCING ARALKYL CYANIDES Ferdinand Dengel, Mannheim, Germany, assignor to Knoll A. G. Chemische Fabriken, Ludwigshafen am Rhine, Germany No Drawing. Application March 22, 1951, Serial No. 217,070

Claims priority, application Germany March 30, 1950 9 Claims. (Cl. 260-465) This invention relates to an improved method of producing nitriles, and more particularly to a method of producing nitriles by replacing a halogen atom attached to a non-aromatic residue, by the cyano group.

It is known to affect said replacement of the halogen atom by the cyano group by reacting the halogen compound at elevated temperature with an alkali cyanide in alcoholic, aqueous-alcoholic, or in aqueous solution. The yields obtained thereby are, however, not very satisfactory, especially when using as starting material compounds with rather loosely bound halogen, such as benzyl chloride and its substitution products; for, in this case side reactions with the solvents used take place quite frequently. As is known, alkali cyanides are hydrolized to a considerable extent in aqueous or aqueous-alcoholic solution, especially at elevated temperature. Said partially hydrolized solutions contain free alkalihydroxide which favorably affects reaction of the halogen compound with the solvent. Thereby the following side-reactions may take place:

R.CH2.halogen+HOH- R.CH2OH +H.hal0gen R.CHz.halogen+HOCHz.R-

R.CHa.O.CH-z.R+H.halogen R.CHz.halogen+HOC2I-I5 R.CH2.0.C2H5+H.ha10gen Said side-reaction may even predominate the desired nitrile formation, the nitrile being then obtained only in very small yield.

It is also not possible to use the correspondingiodo compounds instead of the chloro or bromo compounds when producing nitriles on a large technical scale. For, said iodo compounds are rather expensive. Furthermore, a large number of such iodo compounds are not at all available or can be produced only with great difliculties because they are often readily decomposable.

One object of this invention consists in providing a method whereby the nitrile yield is considerably increased when replacing halogen attached to the aliphatic residue in aralkyl hydrocarbon compounds, by the cyano group. Sometimes it is possible to double or even increase several times the yield over that obtained according to the known methods. In order to achieve this remarkable increase in yield the reaction of the chloro or bromo compound With cyanide is carried out in the presence of a small amount of a soluble metal iodide, such as potassium or sodium iodide, and in an indifferent organic solvent in which the cyanide is sufliciently soluble. Acetone has proved to be especially suitable for this purpose, but other ketones, such as methyl ethyl ketone, diethyl ketone, cyclohexanone and other solvents, may be used likewise. Usually it is sufiicient that the solubility of the cyanide in the organic solvent amounts to 0.ll.0%.

Instead of the metal iodide one may use the corresponding metal bromide, such as potassium bromide or sodium bromide. Thereby the same excellent yields are obtained as with the iodide. Replacement of the expensive metal iodide by the cheaper metal bromide is of special im- T nited States Patent O i 2,734,908 Patented Feb. 14, 1956 ice portance when applying the process of this invention to large scale production.

Only comparatively small amounts of said metal iodides or metal bromides have to be added to the reaction mix ture. Usually amounts of 0.55.0% are sufiicient. In the case of metal bromides amounts of 10.0% or more may be added. Said amounts are based upon the amount of organic halogen compound used as starting material.

When adding said small amounts of alkali iodide to the heretofore used solvents, such as methanol, ethanol, or their mixtures with water, not only no increase in yield takes place, but, on the contrary, the yield is considerably reduced because the side-reactions between halogen compound and solvent are catalytically influenced and favored by the addition of said alkali iodide. On the other hand, when carrying out the reaction in one of the above mentioned indifferent solvents, for instance, in acetone, without adding at the same time a small amount of alkali iodide or alkali bromide, no formation of nitrile takes place because the organic halogen compound does not react with the cyanide in said indilferent solvent and under such conditions. The halogen compound is recovered in unchanged form.

The combination of these two measures, however, namely reaction in the presence of a small amount of a metal iodide or metal bromide and working in an indifferent medium, accomplishes replacement of the halogen atom in the halogen compound by the cyano group and formation of the desired nitrile.

While, according to the known methods, it is possible to obtain nitriles from aliphatic halogen compounds in practically satisfactory yield, said known processes can not be applied successfully to halogenated aralkyl compounds, especially to those in which the halogen in the aliphatic side chain is attached only rather loosely. For instance, halogen compounds, such as anisyl chloride, piperonyl chloride, veratryl chloride and the like, can be converted into nitriles only to 15-50%. But when working according to the process of this invention the corresponding nitriles are obtained in almost quantitative yield from said halogen compounds.

The nitrile formed according to the process of this invention is usually of such a purity that it can be worked up directly and without any further troublesome and expensive recrystallisation or purification into other valuable products. Since the nitriles are usually used as intermediates, for instance, for producing carboxylic acids, amines, or ketones, it is of great advantage that a subsequent purification of said nitriles can be avoided.

The following examples serve to illustrate this invention without, however, limiting the same to them.

Example 1.Benzyl cyanide alcoholic sodium hydroxide solution. After working up.

the saponification mixture, 50.6 g. of phenyl acetic acid, melting at -76 C., are obtained. The yield is about 94% of the theoretical amount calculated for benzy chloride used.

It may be mentioned that according to the well known standard manual of Gattermann-Wieland Die Praxis des organischen Chemikers, page 129 [1947], benzyl cyanide is obtained in a yield of only 77% .of the theoretical amount.

Example 2.Anisyl cyanide (4-mezhoxy benzyl cyanide) 100" g. of pure p-methoxy benzylchloride are dissolved in 600 cc. of dry acetone. 40 g. of sodium cyanide and 3 g, of sodium; iodide are. added to said solution, and the mixture is heated to boiling under reflux on the water bath for. 24 hours. After separating the yellowish-red solution from the. salt mixture by filtration and after evaporating the acetone, .theoily residue is dissolved in ether, the ethereal solutionis washed with water, and dried. After removing the ether by distillation, the crude nitrile residue is subjected to fractional vacuum distillation. 88 g. of anisyLcyanidecorresponding to 94% of the theoretical yield. are obtained as water-clear liquid having a boiling point of 147-150 C./12 mm.

Pschorr, Wolfes, and Buckow, Berichte der deutschen Chemischen Gesellschaft, vol. 33, p. 171 [1900], did not obtain any satisfactory results intheir experiments to produce'pemethoxy benzyl cyanide, starting with anis alcohol, chlorinating the. same, and reacting the chloro compound with potassium. cyanide; on account of. the poor yieldobtained thereby. another methodrof producing said.

nitrile was worked out.

Example 3.Pipernyl' cyanide (3,4-methylene dihydroxy benzyl cyanide) A solution of 25 g. of piperonyl chloride in 150 cc. of acetoneis reacted with 15. g. of sodium cyanide and 1.2 g. ofsodiumiodide while boilingthe mixture for 24 hours. Working upsaid reaction mixture according to Example 1, yields crude piperonyl cyanide in the form of a yellow oil. By saponiiication with an aqueous solution containing 10% of sodium hydroxide andalcohol in a manner known per se, 25.6 g. of homopiperonylic acid, having a melting point of 128-129 C., are obtained. Yield: 96% of the theoretical amount calculated for piperonyl chloride used.

According to the known method described by Mannich and Walther in Archiv der Pharmazie, vol. 265, p. 6 [1927], piperonyl cyanide is obtained in a yield of only 53%.

Example 4.Veratztyl cyanide (3,4-dimerh0xy benzyl cyanide) 30 g. of veratryl chloride aredissolved in 150 cc. of acetone. To this solution there are added 10 g. of sodium cyanide and 0.3 g. of sodium iodide. The mixture is then boiled under reflux for, 24 hours. After filtering off the salts, the filtrate is concentrated by evaporation and the residual crude nitrile is obtained in almost quantitative yield in the formof a yellow oil. Remaining traces of salt are removed therefrom by dissolving the crude prod not in ether and shaking the ethereal solution with water. 27.2 g. of .pureveratryl cyanid'e'melting at 49 C. are obtained by fractional distillation in a vacuum of the residue remaining after drying said ethereal solution and evaporating the ether. Thereby the veratryl cyanide distills at a boilingpoint of 140 C./l. mm. Yield: 95% of the theoretical amount.

Example .-Veratrylcyanide 30 g; of veratryl chloride are dissolved in 180 cc. of methyl ethyl ketone. g. of sodium cyanide and 0.3 g. ofsodium iodide are added to said solution. The mixture is stirred while kept in a thermostatic device at 65 C. for 2 hours. Thereupon thesolvent is; evaporated, the residual. crude nitrile is dissolved in ether, and the ethereal solutioniswashed with water and dried. After evaporating the ether, the residue is subjected to fractional distillation ina-vacuum. At a. boiling point of 140 C./ 1 mm. there are:obtained.26.3 g. of veratryl cyanidecorrespondingto a yield of 92% of'the.theoreticalamount calculated f'or-veratnyl chloride employed.

According to the method of'Kindler and Gehlhaar as described in Archiv der Pharmazie, vol. 274, p. 386

[1936], veratryl cyanide is obtained in a yield of only 52% or 53% respectively.

Example 6.-3-fla0r0-4-meth0xy benzyl cyanide 137 g. of 3-fluoro-4-methoxy benzylchloride are dissolved in 700 cc. of acetone. 59g. of sodium cyanide and 5 g. of sodium iodide are added to said solution, and the mixture is boilediunder reflux on the water bath for 24'hours. The salt precipitate is filtered off by suction, the acetone is evaporated, and the oily evaporation residue is dissolved in ether. Remaining; traces of neutral salts are removed by shaking the etheral solution with Water. The ether is then evaporatedand the residue. is subjected to fractional distillation in a vacuumwhereby the 3-fluoro-4-methoxy benzyl cyanide distills as colorless oil at a boiling point of 158 C./ 10 mm. The oily distillate solidifies to white crystals having. a melting point of 4546 C. Yield: 109 g. corresponding to 82% of thetheoretical amount.

Example 7 .9-cyano. methyl phenanthrene In the manner described in the preceding examples,

9 clt'loro methyl'phenantlirene. is converted into 9-cyano' Example 8.1-cyano-methyl-2-methyl naphthalene 50 g. of freshlydistilled l-chloro methyl-Z-methyl naphthalene (boiling at 154 C./6,mm., melting at 6l-63 C.), obtainedby reacting Z-methyl napthalene with formaldehyde and gaseous hydrochloric acid, are dissolved in 300 cc. of acetone. 20 g. of sodium cyanide and 2.5 g. of sodium-iodideare'added to said solution. The reaction mixture is heated to boilingunder reflux for 24 hours. Thereupon the salt precipitate is filtered oil by suction, the acetone'isdistilled'otf from the filtrate, the residue is taken. up. in.ether, the ethereal solution is washed with water anddried. The ether is then removed by evaporation and the residue is distilled in a vacuum. The crude cyanocompound distills as colorless oil at a boilingpoint of 155 C./ 0.3 mm. The distillate-solidifies immediately to crystals having a melting point of 77 C. Yield: 45 .4g. correspondingto 95.4% of the theoretical amount.

Example 9 .-Veratryl cyanide llO-g. offveratrylf chloride, obtained by chloro meth ylatiorrof g. of"ver atrol, are dissolved-in 750 cc. of acetone. 89 g. ofisodiurncyanide. and 10 g. of sodium bromide areadded'to saidsolution, and the reaction mix-- Example 10 Whenusing in Example 1, instead of 50 g. of benzyl chloride 67 g, of bcnzylbromide, and proceedingin the same manner asdescribed in said'exarnple, 50 g. of phenyl acetic acid corresponding to a yield of 93% are obtained.

Example 11 I UsingOA g: of potassium bromide instead of 0.3 g. of sodium iodide andproceeding as described in Example 4, yields 25.2 g. of pure veratryl cyanide corresponding to a yield of 88%.

Example 12 When using 200 cc. of cyclohexanone instead of 180 cc. of methyl ethyl ketone as in Example and proceeding in the same manner as described in said example, 25.7 g. of veratryl cyanide are obtained corresponding to a yield of 90%.

Of course, many changes and variations in the reaction conditions, the reaction temperature and duration, the solvents used, the starting materials employed, the meth ods of working up the reaction mixture to the desired cyanide compounds, the ways of purifying the same and the like may be made by those skilled in the art in accordance with the principles set forth herein and in the claims annexed hereto.

What I claim is:

l. in a process of producing aralkyl cyanides, the step comprising reacting an aralkyl compound substituted in the aliphatic side chain by halogen, with alkali cyanide in the presence of substantially less than the equimolecular amount of a soluble metal halogenide selected from the group consisting of a metal iodide and a metal bromide, said aralkyl compound being dissolved in a substantially Water-free organic solvent having dissolving power for said alkali cyanide.

2. In a process of producing aralkyl cyanides, the step comprising reacting an aralkyl compound substituted in the aliphatic side chain by halogen, with alkali cyanide in the presence of substantially less than the equimolecular amount of sodium iodide, said aralkyl compound being dissolved in a substantially water-free solvent having dissolving power for said alkali cyanide.

3. In a process of producing aralkyl cyanides, the step comprising reacting an aralkyl compound substituted in the aliphatic side chain by halogen, with alkali cyanide in the presence of substantially less than the equimolecular amount of sodium iodide in an amount between about 0.5% and about 10.0% calculated for the aralkyl halide reacted, said aralkyl compound being dissolved in a substantially water-free organic solvent having dissolving power for said alkali cyanide.

4. In a process of producing aralkyl cyanides, the step comprising heating to boiling under reflux an aralkyl compound substituted in the aliphatic said chain by halogen, with alkali cyanide in the presence of substantially less than the equimolecular amount of a soluble metal halogenide selected from the group consisting of a metal iodide and a metal bromide, said aralkyl compound being dissolved in a substantially water-free organic solvent having dissolving power for said alkali cyanide.

5. In a process of producing aralkyl cyanides, the step comprising reacting an aralkyl compound substituted in the aliphatic side chain by halogen, with alkali cyanide in the presence of substantially less than the equimolecular amount of a soluble metal halogenide selected from the group consisting of a metal iodide and a metal bro mide, said aralkyl compound being dissolved in a substantiaily water-free ketone having dissolving power for said alkali cyanide.

6. In a process of producing aralkyl cyanides, the step comprising heating an aralkyl compound substituted in the aliphatic side chain by halogen, with alkali cyanide in the presence of substantially less than the equimolecular amount of an alkali iodide, said aralkyl compound being dissolved in substantially water-free acetone.

7. in a process of producing a phenyl alkyl cyanide substituted in the phenyl ring by an alkoxy group, the step comprising heating a phenyl alkyl chloride substituted in the phenyl ring by an alkoxy group, with alkali cyanide in the presence of alkali iodide in an amount between about 0.5% and about 10.0% calculated for said phenyl alkyl chloride compound, said phenyl alkyl chloride compound being dissolved in substantially waterfree acetone.

8. In a process of producing a benzyl cyanide substituted in the phenyl ring by an alkoxy group, the step comprising heating a benzyl chloride substituted in the phenyl ring by an alkoxy group, with alkali cyanide in the presence of alkali iodide in an amount between about 0.5% and about 10% calculated for said benzyl chloride compound, said benzyl chloride compound being dissolved in substantially water-free acetone.

9. In a method of producing veratryl cyanide, the steps comprising heating to boiling an acetonic solution of veratryl chloride with sodium cyanide and sodium iodide until substantially all the chlorine of the veratryl chloride has been replaced by the cyano group, and recovering from the reaction mixture the veratryl cyanide formed.

References Cited in the file of this patent UNITED STATES PATENTS 1,672,253 Giles June 5, 1928 1,702,711 Trusler Feb. 29, 1929 2,195,076 Braun Mar. 26, 1940 FOREIGN PATENTS 621,520 Great Britain Apr. 11, 1949 OTHER REFERENCES Hass et al.: Ind. & Eng. Chem, vol. 23, pgs. 352-3 (1931).

Migrdichian: Chem. of Org. Cyanogen Compounds" (ACS Monograph No. 105, Reinhold), pp. 129-130 (1947).

Brintzinger et al.: Chem. Ber., vol. 83, pgs. 141-5 (1950). 

1. IN A PROCESS OF PRODUCING ARALKYL CYANIDES, THE STEP COMPRISING REACTING AN ARALKYL COMPOUND SUBSTITUTED IN THE ALIPHATIC SIDE CHAIN BY HALOGEN, WITH ALKALI CYANIDE IN THE PRESENCE OF SUBSTANTIALLY LESS THAN THE EQUIMOLECULAR AMOUNT OF A SOLUBLE METAL HALOGENIDE SELECTED FROM THE GROUP CONSISTING OF A METAL IODINE AND A METAL BROMIDE, SAID ALKYL COMPOUND BEING DISSOLVED IN A SUBSTANTIALLY WATER-FREE ORGANIC SOLVENT HAVING DISSOLVING POWER FOR SAID ALKALI CYANIDE. 